Taking down Factor XII in the blood to fight Alzheimer's
While the buildup of sticky proteins called amyloid plaques in the brain has been repeatedly linked to Alzheimer's disease, the role of blood in the formation of the condition has been less clear. Researchers at Rockefeller University believe they've now linked an important plasma-based protein called Factor XII to Alzheimer's, which could one day help control symptoms of the disease.
One of the issues with studying the progression of Alzheimer's disease has been that traditionally, by the time symptoms show up in an individual, it's too late to see the steps that caused them. Thanks to the discovery of new genetic markers for a hereditary form of Alzheimer's though, researchers can now examine people genetically predisposed to the condition to see what changes their bodies go through well before symptoms appear. And that's exactly what the RU researchers did.
"It's a devastating disease to have, but it's given us new research opportunities," said Sidney Strickland, co-author on a paper just released about the study. "The first changes observed in these patients are in beta-amyloid levels. The second changes are brain abnormalities related to the vascular system, which can occur 20 years before overt cognitive symptoms appear."
With regard to those vascular system changes, Strickland's lab had previously shown that beta-amyloid, the molecule that leads to the plaques associated with Alzheimer's, was linked to a flood of enzymes that cause inflammation and the coagulation of blood. Now they've isolated a part of that deluge – a blood-clotting compound called Factor XII – and shown that repressing it in mice wards off symptoms of the disease.
In their study, the researchers blocked the gene that makes Factor XII in a portion of mice that had Alzheimer's disease. They found that those mice, compared to a control group, had brains that were more similar to healthy mice and had much less inflammation than mice that did not have Factor XII suppressed. Furthermore, the mice that had been treated showed better cognitive function than those that hadn't had Factor XII knocked back.
The mice were all made to run a maze to find an escape hole. They were trained to find the hole after repeated trials. While healthy mice were able to learn their way out of the maze, those with Alzheimer's weren't able to remember how to accomplish the task. When they were treated with the Factor XII suppressors, however, their success in getting out of the maze increased significantly, although it didn't reach the levels of healthy mice.
As a result, the researchers point out that Factor XII regulation likely won't lead to a cure for Alzheimer's, although it could help scientists develop new early-stage detection strategies and medications to stall the progression of the disease.
"We need to further define what's going on, so we can identify patients with vascular problems and develop a targeted therapy to help that aspect," said Zu-Lin Chen, a senior research associate in the Strickland lab. "We had great improvements in our mice but we didn't fully correct the problem. Alzheimer's is a complex disease, and there are multiple elements involved."
The team's work has been published in the journal Blood.
Source: The Rockefeller University